Alzheimer's disease (AD), the most common cause of dementia in the elderly, is now the fourth major cause of death in the United States. AD is characterized and diagnosed by distinctive neuropathological alterations including extracellular deposits of the B-amyloid (AB)peptide. Epidemiological investigations have demonstrated that AD is a complex, age-related disorder with numerous genetic and environmental etiologies. One of the major difficulties in understanding the relationship between the various genetic, environmental and therapeutic factors that may modify the onset and progression of AD has been the lack of accurate and defined genetic models of the disease. Over the past decade numerous groups have generated transgenic mice using human AD gene fragments. These models, by definition, rely on certain assumptions regarding the fragment of the gene(s) to be expressed as well as the promoter utilized to drive expression of the transgene and are often maintained on ill-defined mixed genetic backgrounds all of which complicate their utility for studying factors that modify AD phenotypes. By contrast, we have focused on developing genomic-based mouse models of AD ("genocopies"), through the introduction of complete copies of human AD genes into the germline of mice and have recently established a genomic-based model in the four different mouse strains whose genomes have been sequenced. Importantly, our recent data demonstrates that genetic background in the mouse dramatically alters both the metabolism and deposition of the AB peptide in the brains of these models. The specific aims of the current proposal are to utilize these unique mouse models to identify in vivo genetic modifiers of AB metabolism and deposition by: 1) Characterization of the age-related molecular, biochemical and neuropathological phenotypes of the four mouse strains. 2) Genetic mapping studies to identify candidate genes that regulate AB metabolism and AB deposition. 3) Candidate gene analysis through gene expression microarray analysis, transgenesis and analysis of the role of the candidate genes in human AD.